The reproductive state of lactation, which occurs in all mammals, is associated with an inhibition of reproductive cyclicity and ovulation due to a suppression of gonadotropin releasing hormone (GnRH), the hypothalamic neuroendocrine neurons regulating reproduction. The focus of our studies is to identify the afferent neuronal pathways activated during lactation by the suckling stimulus that are responsible for the suppression of GnRH neuronal function. This past year, we made the following observations 1) Using neuronal tract tracing techniques and confocal microscopy, we have shown that NPY neurons activated by the suckling stimulus project to areas containing GnRH neurons and make contact with GnRH neuronal processes. These results suggest a possible neuronal mechanism by which suckling inhibits GnRH neuronal activity. 2) The large increase in food intake during lactation most likely occurs in response to substances that signal changes in metabolic activit y, such as leptin (a satiety-inducing substance) and agouti-related transcript (ART, induces obesity). During lactation, blood leptin levels are greatly suppressed, whereas ART expression is increased in the hypothalamus. Current studies in the laboratory are examining the relationship between the changes in leptin and ART and the increase in NPY neuronal activity and food intake. In addition, we are exploring possible interactions between the regulation of food intake and of gonadotropin releasing hormone neuronal activity during lactation. It is well established that many causes of infertility are related to changes in energy homeostasis, such as in exercised-induced amenorrhea and anorexia nervosa. An understanding of the mechanisms by which the suckling stimulus imposes an inhibition on GnRH neuronal function provides information that is relevant to primates (including humans), in which the reproductive neuroendocrine axis regulating ovarian cyclicity is also inhibited. These studies have relevance to women's reproductive health as they will increase our understanding of hypothalamic causes of infertility and provide new approaches for contraception. FUNDING NIH HD14643 PUBLICATIONS Li C, Chen P, Smith MS. The acute suckling stimulus induces expression of Neuropeptide Y (NPY) in cells in the dorsomedial hypothalamus and increases NPY expression in the arcuate nucleus. Endocrinology 139:1645-1652, 1998. Li C, Chen P, Smith MS. Neuropeptide Y (NPY) neurons in the arcuate nucleus (ARH) and dorsomedial nucleus (DMH), areas activated during lactation, project to the paraventricular nucleus of the hypothalamus (PVH). Reg Peptides 75-76:93-100, 1998. Li C, Chen P, Smith MS. Neuropeptide Y (NPY) and tuberinfundibular dopamine (TIDA) are altered during lactation role of prolactin. Endocrinology 140 118-123,1999. Grove KL, Smith MS. Resistance of the hippocampus in the lactating rat to N-methyl-D-aspartate (NMDA)-mediated excitation is not due to a nonfunctional receptor system. Brain Res 814:157-163, 1998. Grove KL, Smith MS. 3?-hydroxysteroid dehydrogenase (3? -HSD) and mRNA distribution in the rat brain. In The Endocrine Society Program & Abstracts 80th Annual Meeting (held in New Orleans, LA, June 24-27, 1998), p 493 (abstract #P3-527). Brogan RS, Kuper J, Duncan JS, Trayhurn P, Smith MS. Serum leptin levels during lactation are related to the metabolic drain of milk projection lack of correlation to serum LH. In The Endocrine Society Program & Abstracts 80th Annual Meeting (held in New Orleans, LA, June 24-27, 1998), p 349 (abstract #P2-478). Chen P, Haskell-Luevano C, Cone RD, Smith MS. Coexpression of agouti-related transcript (ART) and neuropeptide Y (NPY) in the hypothalamic arcuate nucleus of female rats during the estrous cycle and lactation. In the Endocrine Society Program & Abstracts 80th Annual Meeting (held in New Orleans, LA, June 24-27, 1998), p 521 (abstract #P3-663). Li C, Chen P, Smith MS. Anatomical interactions between neuropeptide Y neurons from arcuate nucleus of the hypothalamus (ARH-NPY) and the gonadotropin-releasing hormone (GnRH) in the hypothalamus. In The Endocrine Society Program & Abstracts 80th Annual Meeting (held in New Orleans, LA, June 24-27, 1998), p 59 (abstract #OR5-5). Li C, Chen P, Smith MS. Neuropeptide Y neurons from the arcuate nucleus of the hypothalamus (ARH-NPY) directly project to corticotropin releasing hormone (CRF) neurons in the paraventricular nucleus (PVH). Soc Neurosci Abstr 24(pt 1):369, 1998 (abstract #146.8). Brogan RS, Grove KL, Smith MS. Leptin receptor expression during lactation. Society for the Study of Reproduction 58(suppl 1):96 (abstract #81).